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Antibody–Cytotoxic Compound Conjugates for Oncology

  • Carol A. Vater
  • Victor S. Goldmacher
Chapter
Part of the Macromolecular Anticancer Therapeutics book series (CDD&D)

Abstract

The original rationale underlying the development of antibody–cytotoxic compound conjugates (ACC) was to improve the selectivity of cytotoxic anti-cancer drugs by targeting them to tumors with the help of antibodies. The ACC concept has since matured significantly, following several key advancements: (i) generation of technologies for creating humanized and fully human monoclonal antibodies; (ii) development of conjugatable cytotoxic compounds of sufficient potency to be effective in eradicating tumor cells in an antigen-selective manner; (iii) advances in knowledge and antibody engineering to maximize anti-tumor cell effect or functions; and (iv) optimization of linkers used to conjugate cytotoxic compounds to antibodies in order to achieve both maximal stability of the ACC in the circulation and maximal release of the active cytotoxic component within targeted tumor cells. In this chapter we will focus on our present understanding of what makes an effective ACC for the treatment of oncology patients. We will discuss parameters that are important for the selection of antigen targets, antibodies, cytotoxic compounds, and linkers, and current approaches being taken to further improve the efficacy of ACCs. In addition, we will review preclinical and clinical experiences with the current generation of ACCs.

Keywords

Cancer Stem Cell Antigen Expression Target Antigen Anaplastic Large Cell Lymphoma Gemtuzumab Ozogamicin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

ACC

Antibody–cytotoxic compound conjugate

ADC

Antibody–drug conjugate

ADCC

Antibody-dependent cellular cytotoxicity

AML

Acute myelogenous leukemia

CDC

Complement-dependent cytotoxicity

CDR

Complementarity determining region

CR

Complete response

CSC

Cancer stem cell

DM1

N-methyl-N-[3-mercapto-1-oxopropyl]-l-alanine ester of maytansinol

DM4

N-methyl-N-[4-mercapto-4-methyl-1-oxopentyl]-l-alanine ester of maytansinol

FcRn

neonatal Fc receptor

FcγR

IgG Fc receptor

FDA

US Food and Drug Administration

IHC

Immunohistochemistry

MDR

Multi-drug resistance

MGBA

Minor groove-binding alkylating agent

MMAE

monomethylauristatin E

MMAF

monomethylauristatin F

MTD

Maximum tolerated dose

PR

Partial response

PSMA

Prostate-specific membrane antigen

SD

Stable disease

T-DM1

Trastuzumab-SMCC-DM1

Notes

Acknowledgments

We thank our colleagues, Robert Lutz, John Lambert, Rajeeva Singh, Peter Park, Daniel Tavares, Ravi Chari, Yelena Kovtun, and Carol Hausner for critical reading of the manuscript and Yelena Kovtun for drawing the figures.

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Carol A. Vater
    • 1
  • Victor S. Goldmacher
    • 1
  1. 1.ImmunoGen, Inc.WalthamUSA

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